• Extracellular fluid calcium concentration is very tightly controlled and normally stays near 9.4 mg/dL = 2.4 mmol/L.
• This precise control is important because calcium is essential for:
  • Skeletal, cardiac, and smooth muscle contraction
  • Blood clotting
  • Transmission of nerve impulses
• Excitable cells, especially neurons, are very sensitive to changes in calcium:
  • Hypercalcemia → progressive depression of the nervous system
  • Hypocalcemia → increased nervous system excitability
• Only about 0.1% of total body calcium is present in extracellular fluid.
• About 1% is present inside cells and their organelles.
• Almost all the remaining calcium is stored in bones.
• Therefore, bones act as a large calcium reservoir:
  • Excess calcium → stored in bone
  • Low extracellular calcium → calcium released from bone
• Body phosphate distribution is:
  • About 85% → bones
  • About 14%–15% → cells
  • <1% → extracellular fluid
• Extracellular phosphate is not regulated as precisely as calcium.
• However, phosphate has important functions and is controlled by many of the same factors that regulate calcium.

CALCIUM IN THE PLASMA AND INTERSTITIAL FLUID

• Plasma calcium exists in three forms (Fig. 80.1):
  • 41% = about 1 mmol/L
    • Bound to plasma proteins
    • Cannot diffuse through capillary membranes.
  • 9% = about 0.2 mmol/L
    • Can diffuse through capillary membranes.
    • Bound to anions such as citrate and phosphate.
    • It is not ionized.
  • 50%
    • Diffusible through capillary membranes.
    • Present as ionized calcium (Ca²⁺).
• Normal ionized calcium concentration in plasma and interstitial fluid is about 1.2 mmol/L.
• Because calcium is divalent: 1.2 mmol/L Ca²⁺ × 2 = 2.4 mEq/L
• Ionized calcium is therefore about one-half of total plasma calcium.
• Ionized Ca²⁺ is the physiologically important form for most calcium functions, including effects on:
  • Heart
  • Nervous system
  • Bone formation

KEY CONCEPT

• Normal total plasma calcium ≈ 9.4 mg/dL = 2.4 mmol/L.
• Bone = major calcium reservoir.
• Hypercalcemia → nervous system depression.
• Hypocalcemia → nervous system excitation.
• Plasma calcium:
  • 41% protein-bound
  • 9% nonionized but diffusible
  • 50% ionized
• Ionized Ca²⁺ ≈ 1.2 mmol/L = 2.4 mEq/L and is the most physiologically active form.

Conceptual Examples

• Low extracellular calcium:
  ↓ Ca²⁺ → bone releases calcium → helps restore extracellular calcium.
• High extracellular calcium:
  ↑ Ca²⁺ → excess calcium stored in bone → helps limit the rise.
• Nervous system:
  ↓ Ca²⁺ → more nervous system excitability.
  ↑ Ca²⁺ → more nervous system depression.
• Plasma calcium:
  Total calcium → only about 50% is ionized Ca²⁺ → this is the form most important for normal physiological actions.

INORGANIC PHOSPHATE IN THE EXTRACELLULAR FLUIDS

• In plasma, inorganic phosphate is mainly present in two forms:
  • HPO₄²⁻ ≈ 1.05 mmol/L
  • H₂PO₄⁻ ≈ 0.26 mmol/L
• When total extracellular phosphate increases, both phosphate forms increase.
• Changes in extracellular pH alter their relative amounts:
  • Acidosis → ↑ H₂PO₄⁻ and ↓ HPO₄²⁻
  • Alkalosis → ↓ H₂PO₄⁻ and ↑ HPO₄²⁻
• Because exact measurement of each phosphate ion is difficult, total plasma phosphate is usually expressed as mg of phosphorus/dL of blood.
• Average total inorganic phosphorus is about 4 mg/dL.
• Normal values are approximately:
  • Adults: 3–4 mg/dL
  • Children: 4–5 mg/dL

KEY CONCEPT

• Plasma phosphate exists mainly as HPO₄²⁻ and H₂PO₄⁻.
• Acidic pH favors H₂PO₄⁻.
• Alkaline pH favors HPO₄²⁻.
• Normal inorganic phosphorus:
  • Adults → 3–4 mg/dL
  • Children → 4–5 mg/dL

Conceptual Examples

• Acidosis:
  ↓ pH → ↑ H₂PO₄⁻ + ↓ HPO₄²⁻
• Alkalosis:
  ↑ pH → ↑ HPO₄²⁻ + ↓ H₂PO₄⁻
• Normal adult:
  Total inorganic phosphorus ≈ 3–4 mg/dL.

NONBONE PHYSIOLOGICAL EFFECTS OF ALTERED CALCIUM AND PHOSPHATE CONCENTRATIONS IN THE BODY FLUIDS

• Large changes in extracellular phosphate usually cause little immediate physiological effect.
• In contrast, even small changes in extracellular Ca²⁺ can cause major immediate effects.
• Chronic hypocalcemia or hypophosphatemia also reduces bone mineralization.

Hypocalcemia Causes Nervous System Excitement and Tetany

• When extracellular Ca²⁺ falls, the nervous system becomes increasingly excitable.
• Low Ca²⁺ increases neuronal membrane permeability to Na⁺.
• Na⁺ therefore enters more easily, so action potentials are triggered more easily.
• When plasma Ca²⁺ falls to about 50% below normal, peripheral nerves may begin to fire spontaneously.
• These nerve impulses stimulate skeletal muscles and produce tetanic contractions.
• Therefore: ↓ Ca²⁺ → ↑ Na⁺ permeability → ↑ nerve excitability → spontaneous impulses → tetany
• Hypocalcemia can also increase brain excitability and occasionally cause seizures.
• Tetany often appears first in the hand as carpopedal spasm (Fig. 80.2).
• Tetany usually occurs when total blood calcium falls from about 9.4 mg/dL to 6 mg/dL.
• A calcium level around 4 mg/dL is usually lethal.
• In extreme hypocalcemia, additional effects may include:
  • Marked dilation of the heart
  • Changes in cellular enzyme activity
  • Increased membrane permeability
  • Impaired blood clotting

KEY CONCEPT

• Phosphate changes → relatively few immediate effects.
• Calcium changes → major immediate effects.
• Hypocalcemia → ↑ neuronal Na⁺ permeability → ↑ excitability → tetany.
• ~6 mg/dL calcium → tetany
• ~4 mg/dL calcium → usually lethal

Conceptual Examples

• Low calcium:
  ↓ Ca²⁺ → nerves fire more easily → muscle tetany.
• Hand finding:
  Hypocalcemia → tetany begins in the hand → carpopedal spasm.
• Very severe hypocalcemia:
  Markedly low Ca²⁺ → seizures, impaired clotting, and potentially lethal effects.

Hypercalcemia Depresses Nervous System and Muscle Activity

• When blood calcium rises above normal, the nervous system becomes depressed.
• Central nervous system reflexes become sluggish.
• Increased Ca²⁺ also causes:
  • Shortened QT interval
  • Reduced appetite
  • Constipation
• Constipation probably occurs because high Ca²⁺ decreases contraction of the gastrointestinal muscle walls.
• These effects begin when blood calcium rises above about 12 mg/dL.
• They become marked above about 15 mg/dL.
• Above about 17 mg/dL, calcium phosphate crystals may precipitate throughout the body.

ABSORPTION AND EXCRETION OF CALCIUM AND PHOSPHATE

Intestinal Absorption and Fecal Excretion of Calcium and Phosphate

• Normal daily intake is approximately:
  • Calcium → 1000 mg/day
  • Phosphorus → 1400 mg/day
• Calcium is normally poorly absorbed from the intestine.
• Vitamin D increases intestinal calcium absorption.
• About 40% = 400 mg/day of ingested calcium is absorbed.
• About 200 mg/day of calcium also enters the intestine through gastrointestinal secretions and shed mucosal cells.
• Therefore, about 80% = 800 mg/day of daily calcium intake is excreted in feces (Fig. 80.3).
• Phosphate is absorbed much more easily.
• Nearly 80% of ingested phosphate is absorbed from the intestine (Fig. 80.4).
• The kidneys normally reabsorb about 98% of filtered calcium, while about 200 mg/day is excreted in urine.
• At least 90% of filtered calcium is reabsorbed in:
  • Proximal tubules
  • Loops of Henle
  • Early distal tubules
• Reabsorption of the remaining 10% in the late distal tubules and early collecting ducts varies according to blood Ca²⁺ concentration.
• When blood Ca²⁺ is low → calcium reabsorption increases → almost no calcium is lost in urine.
• When blood Ca²⁺ rises even slightly → urinary calcium excretion increases markedly.
• PTH is the most important factor controlling this distal calcium reabsorption and therefore calcium excretion.
• Renal phosphate excretion works by an overflow mechanism.
• When plasma phosphate is below about 1 mmol/L:
  • Almost all filtered phosphate is reabsorbed.
  • Almost no phosphate appears in urine.
• When plasma phosphate rises above 1 mmol/L, phosphate excretion increases in proportion to the rise.
• Normally, about 10%–15% of filtered phosphate is excreted in urine.
• Therefore, the kidneys regulate extracellular phosphate by adjusting phosphate excretion according to plasma phosphate concentration and filtration.
• PTH greatly increases renal phosphate excretion and therefore helps regulate both plasma phosphate and calcium.

KEY CONCEPT

• Hypercalcemia → nervous system depression + sluggish reflexes + shortened QT + constipation.
• >12 mg/dL → symptoms begin.
• >15 mg/dL → effects become marked.
• >17 mg/dL → calcium phosphate precipitation may occur.
• Vitamin D promotes intestinal calcium absorption.
• Kidneys reabsorb about 98% of filtered calcium.
• PTH → controls distal calcium reabsorption and increases phosphate excretion.
• Plasma phosphate <1 mmol/L → almost complete renal reabsorption.

Conceptual Examples

• High calcium:
  ↑ Ca²⁺ → depressed nervous and muscle activity → sluggish reflexes + constipation.
• Low blood calcium:
  ↓ Ca²⁺ → kidneys increase Ca²⁺ reabsorption → less calcium lost in urine.
• High blood calcium:
  ↑ Ca²⁺ → ↓ renal reabsorption → more calcium excreted in urine.
• Phosphate overflow:
  Plasma phosphate rises above 1 mmol/L → kidneys excrete more phosphate → helps control extracellular phosphate.
• PTH:
  ↑ PTH → more calcium conserved + more phosphate excreted.

Figure 80.3 — Calcium Balance in the Body

Easiest Concept

Think of extracellular fluid (ECF) as the central calcium pool. Calcium continuously moves between the intestine, blood/ECF, cells, bone, and kidneys.

• Calcium intake = 1000 mg/day
  • We eat about 1000 mg calcium/day.
  • Only 400 mg/day is absorbed from intestine into ECF.
  • About 200 mg/day is secreted back from ECF into intestine.
  • Therefore, 800 mg/day leaves in feces.
• Extracellular fluid = 1300 mg
  • This is the small, rapidly regulated calcium pool connecting all organs.
• Cells = 13,000 mg
  • Calcium can move from ECF into cells and back again.
• Bone = 1,000,000 mg
  • Bone is the huge calcium storehouse.
  • Deposition = 500 mg/day: ECF → bone.
  • Resorption = 500 mg/day: bone → ECF.
  • Because both are equal, there is no net bone calcium change in normal balance.
• Kidneys
  • About 9980 mg/day of calcium is filtered from blood.
  • About 9780 mg/day is reabsorbed back into blood.
  • Therefore only 200 mg/day appears in urine.
  • So kidneys filter a lot but save almost all of it.

Why is the body in calcium balance?

Daily intake = 1000 mg

Daily loss:

Feces 800 mg + Urine 200 mg = 1000 mg

So:

Calcium intake = Calcium excretion

🔑 KEY CONCEPT

1000 mg eaten → most leaves in feces → only 200 mg/day normally leaves through urine.

Bone = main calcium reservoir
ECF = central exchange pool
Kidney = fine controller of calcium loss

One-line memory

“Intestine absorbs calcium, bone stores it, kidneys save it, and feces remove most of what we eat.”

Figure 80.4 — Phosphate Balance in the Body

Easiest Concept

Think of extracellular fluid (ECF) as the central phosphate pool. Phosphate continuously moves between the intestine, cells, bone, and kidneys.

1. Intestine — phosphate comes in

• Phosphate intake = 1400 mg/day
• 1100 mg/day is absorbed from intestine → ECF.
• 200 mg/day is secreted back from ECF → intestine.
• 500 mg/day leaves in feces.

So the net phosphate absorbed into the body = 900 mg/day.

2. Extracellular fluid — central exchange pool

• ECF contains only about 500 mg phosphate.
• It connects phosphate exchange with cells, bone, intestine, and kidneys.

3. Cells — large phosphate store

• Cells contain about 100,000 mg phosphate.
• Phosphate moves ECF ↔ cells.
• Cells need phosphate especially for ATP, nucleic acids, and cellular metabolism.

4. Bone — biggest phosphate store

• Bone contains about 600,000 mg phosphate.
• Deposition = 200 mg/day: ECF → bone.
• Resorption = 200 mg/day: bone → ECF.
• Because both are equal, there is no net change in bone phosphate in normal balance.

5. Kidneys — main regulator

• Kidneys filter 7000 mg/day.
• They reabsorb 6100 mg/day.
• Therefore:

7000 − 6100 = 900 mg/day in urine

So kidneys control phosphate balance mainly by changing how much filtered phosphate is reabsorbed.

Why is the person in phosphate balance?

Daily intake = 1400 mg

Daily loss:

Feces 500 + Urine 900 = 1400 mg/day

Therefore:

Phosphate intake = Phosphate excretion

🔑 KEY CONCEPT

1400 mg eaten → 900 mg net absorbed → kidneys excrete 900 mg → body phosphate stays balanced.

Bone = largest store
Cells = large intracellular store
ECF = small central pool
Kidneys = major controller of phosphate excretion

One-line memory

“Intestine absorbs phosphate → bone and cells store/exchange it → kidneys control how much leaves in urine.”

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